IgE-mediated food allergy affects approximately 5-8% of the US population, and there is no approved treatment. The current management strategy consists of allergen avoidance, but accidental ingestions are a common experience for patients. Severity of reactions is not predictable, and can range from mild hives to life- threatening systemic anaphylaxis. Sensitization commonly occurs in the first year of life, and the most predictive risk factor for food allergy is eczema. A developing paradigm is that exposure to foods via household dust promotes epicutaneous sensitization to foods in children with eczema, while dietary avoidance prevents the normal development of oral tolerance. Based on preliminary data, we hypothesize that inflammatory signals from the skin may also contribute to sensitization to foods encountered by the oral route. Using a model of tape-stripping that mimics the excoriations of atopic dermatitis, we observed that a single episode of mild skin damage leads to a significant change in the innate immune milieu of the small intestine. There is an induction of Th2 cytokine expression by resident innate and progenitor cells of the gastrointestinal tract, as well as an influx of innate cells into the inductive sites of the mucosa immune system. Furthermore, tape stripping in the absence of epicutaneous allergen exposure supports the generation of allergic symptoms when mice are repeatedly fed with the antigen. Based on our preliminary data, we hypothesize that signals generated from a compromised skin barrier act systemically to release progenitors from the bone marrow that home to the gastrointestinal tissues, and in addition drive an innate Th2 response from resident cells of the gastrointestinal tissues. This biased innate immune milieu thereby promotes IgE class switch in the mucosal tissues and impairs the development of oral tolerance. We will test this hypothesis in two specific aims. In the first aim, we will determine the mechanism by which damage to the skin leads to an altered immune milieu in the gastrointestinal tissues. We will examine the impact of mild tape stripping-induced injury on innate and progenitor cells in bone marrow, blood, skin, and gastrointestinal tract tissues, and study their cytokine expression using reporter mice. We will determine the role of skin cytokines in driving this innate immune response in the gastrointestinal tract. In the next aim we will determine the functional consequence of this altered immune milieu on the development of tolerance or sensitization to food antigens using mouse models of food allergy. Furthermore, we will examine the impact of the altered immune milieu on generation of Tfh cells and Tregs as well as class switch to IgE. Successful completion of our aims will provide us with a mechanistic understanding of the role of the skin in development of food allergy, and will help us to design appropriate strategies for the prevention of food allergy in early life.